DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer.
DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer.
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DOI：
10.1158/0008-5472.can-17-1570
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发表时间：
2017-12-01
期刊：
影响因子：
11.2
通讯作者：
Raychaudhuri P
中科院分区：
文献类型：
--
作者：
Huang S;Fantini D;Merrill BJ;Bagchi S;Guzman G;Raychaudhuri P
Wnt/β-连环蛋白信号通路的失调会促进结直肠癌 (CRC) 的发展，但对该通路的了解仍然不完整。在此，我们报道损伤特异性 DNA 结合蛋白 DDB2 对于 β-catenin 介导的 RNF43 激活至关重要，RNF43 通过去除细胞表面的 Wnt 受体来限制 Wnt 信号传导。在人增生性结肠病灶中观察到 DDB2 和 RNF43 表达降低。 DDB2 在 Rnf43 基因的上游位点招募 EZH2 和 β-catenin，从而能够与 Rnf43 内含子中远处的 TCF4/β-catenin 结合位点发生功能性相互作用。 DDB2 的这种新活性是 RNF43 作为 Wnt 信号传导负反馈调节器的功能所必需的。 DDB2 基因缺陷的小鼠表现出对结肠肿瘤发展的易感性增加，这与表达 Wnt 受体的细胞丰度较高和下游 Wnt 通路的激活程度较高有关。我们的研究结果表明，DDB2 既是 Wnt 信号传导的伙伴，又是调节者，在抑制结肠癌的发展中发挥着重要作用。
Deregulation of the Wnt/β-catenin signaling pathway drives the development of colorectal cancer (CRC) but understanding of this pathway remains incomplete. Here we report that the damage-specific DNA-binding protein DDB2 is critical for β-catenin-mediated activation of RNF43, which restricts Wnt-signaling by removing Wnt receptors from the cell surface. Reduced expression of DDB2 and RNF43 was observed in human hyperplastic colonic foci. DDB2 recruited EZH2 and β-catenin at an upstream site in the Rnf43 gene, enabling functional interaction with distant TCF4/β-catenin binding sites in the intron of Rnf43. This novel activity of DDB2 was required for RNF43 function as a negative feedback regulator of Wnt-signaling. Mice genetically deficient in DDB2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of the Wnt receptor-expressing cells and greater activation of the downstream Wnt-pathway. Our results identify DDB2 as both a partner and regulator of Wnt-signaling with an important role in suppressing colon cancer development.